Late-onset Alzheimer's disease (LOAD) is the most common cause of dementia in the elderly. Despite evidence for a substantial genetic component, much of the risk for LOAD remains unexplained. Using plasma amyloid 8 peptide (AB)as a quantitativegenetic marker, we recently identified linkage to a locus on chromosome 10that increases the risk for LOAD by elevating ABlevels. Our aims are to identify this novel LOAD risk gene on chromosome 10 and to characterize its effects on the metabolism of A8. We will use single nucleotide polymorphism (SNP)-based linkage and association studies in LOAD families and case-control groups to narrow the linkage region. We will continue to use the A8 phenotype to group the subjects according to their phenotypes, thus enhancing homogeneity in the study group and enriching the genetic association. This will also allow the evaluation of candidate genes at a mechanistic level, as the causative mutation in the risk gene is expected to increase A8 and the risk for LOAD. Once the gene is identified,further studies are required to determine its mechanism of action and frequency in the general population. These studies could potentially provide new insights to the pathogenesis of AD, lead to the discovery of novel therapeutic targets and allow for the identificationof "at risk" people by using plasma A6 as a biomarker.